The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3' kinase

Saijun Fan, Yong Xian Ma, Ji An Wang, Ren Qi Yuan, Qinghui Meng, Yijan Cao, John J. Laterra, Itzhak D. Goldberg, Eliot M. Rosen

Research output: Contribution to journalArticlepeer-review

Abstract

Scatter factor (SF) [aka. hepatocyte growth factor (HGF)] (designated HGF/SF) is a multifunctional cytokine that stimulates tumor cell invasion and angiogenesis. We recently reported that HGF/SF protects epithelial and carcinoma cells against cytotoxicity from DNA-damaging agents and that HGF/SF-mediated cytoprotection was associated with up-regulation of the anti-apoptotic protein Bcl-X(L) in cells exposed to adriamycin. We now report that in addition to blocking apoptosis, HGF/SF markedly enhances the repair of DNA strand breaks caused by adriamycin or gamma radiation. Constitutive expression of Bcl-X(L) in MDA-MB-453 breast cancer cells not only simulated the HGF/SF-mediated chemoradioresistance, but also enhanced the repair of DNA strand breaks. The ability of HGF/SF to induce both chemoresistance and DNA repair was inhibited by wortmannin, suggesting that these activities of HGF/SF are due, in part, to a phosphatidylinositol-3'-kinase (PI3K) dependent signaling pathway. Consistent with this finding, HGF/SF induced the phosphorylation of c-Akt (protein kinase-B), a PI3K substrate implicated in apoptosis inhibition; and an expression vector encoding a dominant negative kinase inactive Akt partially but significantly inhibited HCF/SF-mediated cell protection and DNA repair. These findings suggest that HGF/SF activates a cell survival and DNA repair pathway that involves signaling through PI3K and c-Akt and stabilization of the expression of Bcl-X(L); and they implicate Bcl-X(L) in the DNA repair process.

Original languageEnglish (US)
Pages (from-to)2212-2223
Number of pages12
JournalOncogene
Volume19
Issue number18
DOIs
StatePublished - Apr 27 2000

Keywords

  • Adriamycin (doxorubicin)
  • Breast cancer
  • HGF/SF
  • Hepatocyte growth factor (HGF)
  • Scatter factor (SF)
  • c-Met

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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